Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from an absolute or relative deficiency of insulin. The chronic hyperglycemia of diabetes is associated with long-term tissue damage, especially of the eyes, kidneys, nerves, heart and blood vessels. Type 2 or non-insulin-dependent diabetes mellitus is the most common form of diabetes, affecting about 15 million people in the United States. Genetic factors play an important role in the development of type 2 diabetes and the overall aim of this application is to identify the genes that are responsible for type 2 diabetes and then to determine how they contribute to the pathogenesis of this disorder. During the present funding period, research carried out under the auspices of this grant has shown that linkage studies using affected sib pairs without parents can be used to localize genes for type 2 diabetes. We have mapped the major type 2 diabetes susceptibility gene in Mexican Americans (gene symbol, NIDDM1), a gene which may account for 30 percent of the familial clustering of type 2 diabetes in this population, to the region of the markers D2S125-D2S140. Our studies also provided evidence for other susceptibility genes of smaller effect than NIDDM1. This is a continuation of collaborative studies between investigators at The University of Chicago, the University of Texas Health Science Center at Houston and Virginia Mason Research Center to identify genes for type 2 diabetes. The aim in the first funding cycle was to map the genes for type 2 diabetes. We have made major progress toward reaching this goal and now propose to make the natural transition from genetic linkage studies to identification and functional characterization of NIDDM1 and other type 2 diabetes genes. Studies being carried out at the University of Chicago will focus on NIDDM1 whereas those at the University of Texas Health Science Center at Houston and Virginia Mason Research Center will involve other regions containing putative type 2 diabetes genes. The identification and characterization of the genes for type 2 diabetes will lead to a better understanding of the molecular basis of this disorder, thereby providing the basis for new approaches for prevention and treatment based on the nature of the underlying molecular defect.